Y chromosome loss in cancer drives growth by evasion of adaptive immunity

Simple Summary Research on leukemia has often led to novel approaches in clinical practice. Cytogenetical and molecular markers have been introduced in treatment protocols contributing to better stratification of leukemia patients in specific prognostic groups and patient-tailored therapy. However, the next step concerns modern hematology. Omics-profiling of leukemia patients is needed to complete the information of all key players which influence the course of the disease. There is no doubt that regulatory RNAs, among which lncRNAs, belong to those key players. Knowledge of the role of lncRNAs in leukemias is not sufficient and the research in that field needs to be increased. This would enable the design of innovative targeted-therapeutics, thus opening the doors wide for personalized medicine in hematological malignancies. Abstract Leukemia is a heterogenous group of hematological malignancies categorized in four main types (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Several cytogenetic and molecular markers have become a part of routine analysis for leukemia patients. These markers have been used in diagnosis, risk-stratification and targeted therapy application. Recent studies have indicated that numerous regulatory RNAs, such as long non-coding RNAs (lncRNAs), have a role in tumor initiation and progression. When it comes to leukemia, data for lncRNA involvement in its etiology, progression, diagnosis, treatment and prognosis is limited. The aim of this review is to summarize research data on lncRNAs in different types of leukemia, on their expression pattern, their role in leukemic transformation and disease progression. The usefulness of this information in the clinical setting, i.e., for diagnostic and prognostic purposes, will be emphasized. Finally, how particular lncRNAs could be used as potential targets for the application of targeted therapy will be considered.

/pdf/diagnostic-and-therapeutic-implications-of-long-non-coding-21qsd9g0.pdf

Diagnostic and Therapeutic Implications of Long Non-Coding RNAs in Leukemia

Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications.

Accurate orchestration of gene expression is critical for the process of normal hematopoiesis, and dysregulation is closely associated with leukemogenesis. Epigenetic aberration is one of the major causes contributing to acute myeloid leukemia (AML), where chromosomal rearrangements are frequently found. Increasing evidences have shown the pivotal roles of histone deacetylases (HDACs) in chromatin remodeling, which are involved in stemness maintenance, cell fate determination, proliferation and differentiation, via mastering the transcriptional switch of key genes. In abnormal, these functions can be bloomed to elicit carcinogenesis. Presently, HDAC family members are appealing targets for drug exploration, many of which have been deployed to the AML treatment. As the majority of AML events are associated with chromosomal translocation resulting in oncogenic fusion proteins, it is valuable to comprehensively understand the mutual interactions between HDACs and oncogenic proteins. Therefore, we reviewed the process of leukemogenesis and roles of HDAC members acting in this progress, providing an insight for the target anchoring, investigation of hyperacetylated-agents, and how the current knowledge could be applied in AML treatment.

/pdf/roles-of-histone-deacetylases-in-acute-myeloid-leukemia-with-5mt2xd9nde.pdf

Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins.

Role of cell-free DNA in haematological malignancies.

To explore the characteristics and prognostic significance of genetic mutations in acute myeloid leukemia (AML), we screened the gene mutation profile of 171 previously untreated AML patients using a next-generation sequencing technique targeting 127 genes with potential prognostic significance. A total of 390 genetic alterations were identified in 149 patients with a frequency of 87.1%. Younger age and high sensitivity to induction chemotherapy were associated with a lower number of mutations. NPM1 mutation was closely related to DNMT3A and FLT3-internal tandem duplication (FLT3-ITD) mutations, but mutually exclusive with ASXL1 mutation and CEBPAdouble mutation . In univariate analysis, ASXL1 or TET2 mutation predicted shorter overall survival (OS) or relapse-free survival (RFS), DNMT3A, FLT3-ITD, or RUNX1 mutation predicted a higher likelihood of remission-induction failure, whereas NRAS mutation or CEBPAdouble mutation predicted longer OS. Concurrent DNMT3A, FLT3-ITD, and NPM1 mutations predicted shorter OS. Hypomethylation agents could improve the OS in patients with DNA methylation-related mutations. According to multivariate analysis, TET2 mutation was recognized as an independent prognostic factors for RFS. In summary, our study provided a detailed pattern of gene mutations and their prognostic relevance in Chinese AML patients based on targeted next-generation sequencing screening.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.3467

Characteristics and prognostic significance of genetic mutations in acute myeloid leukemia based on a targeted next-generation sequencing technique

We have reported the genetic mutation profile in previously untreated acute myeloid leukemia (AML) patients using a targeted NGS screening method. In this study, we evaluated the characteristics and prognostic significance of gene mutations in refractory/relapsed (R/R) AML patients by comparing their gene mutation spectrum to those newly diagnosed. The frequencies of tumor suppressor mutations were increased, while the mutation frequencies of nucleophosmin and spliceosome complex were decreased in relapsed AML. The frequency of FLT3-ITD mutation was increased, while that of CEBPA biallelic mutation decreased in refractory AML. Activated signaling mutations predicted a lower complete remission rate. FLT3-ITD mutation predicted an inferior overall survival after relapse. DNMT3A mutation predicted an inferior relapse-free survival in R/R AML. These findings may shed light on the molecular mechanism study of leukemia refractory or relapse and provide new guidance for the dynamic risk assessment of AML.

Difference in gene mutation profile in patients with refractory/relapsed versus newly diagnosed acute myeloid leukemia based on targeted next-generation sequencing.

Anaplastic lymphoma kinase (ALK) fusion is present in approximately 2-7% of patients with lung adenocarcinoma. ALK fusion-positive patients can benefit from targeted therapy. We herein report a 53-year-old Chinese male patient diagnosed as lung adenocarcinoma with a smoking history. Next-generation sequencing was performed to detect somatic mutations of oncogenic drivers and tumor suppressor genes in plasma-derived circulating tumor DNA using an ultra-deep 160-gene panel. A novel HPCAL1-ALK fusion variant was identified in the patient responding to ALK inhibitor treatments, and the fusion variant was also confirmed by fluorescence in situ hybridization and immunohistochemical. Our study expands the mutational spectrum of ALK fusion variants and provides options for the precise treatment of such patients.

/pdf/responses-to-alk-inhibitor-treatments-in-a-patient-with-non-2q76si5c6z.pdf

Responses to ALK Inhibitor Treatments in a Patient with Non-Small Cell Lung Cancer Harboring a Novel HPCAL1-ALK Fusion Variant: A Case Report.

Mosaic loss of chromosome Y (mLOY) in blood cells is one of the most frequent chromosome alterations in adult males. It is strongly associated with clonal hematopoiesis, hematopoietic malignancies, and other hematopoietic and nonhematopoietic diseases. However, whether there is a causal relationship between mLOY and human diseases is unknown. Here, we generated mLOY in murine hematopoietic stem and progenitor cells (HSPCs) with CRISPR/Cas9 genome editing. We found that mLOY led to dramatically increased DNA damage in HSPCs. Interestingly, HSPCs with mLOY displayed significantly enhanced reconstitution capacity and gave rise to clonal hematopoiesis in vivo. mLOY, which is associated with AML1-ETO translocation and p53 defects in patients with acute myeloid leukemia (AML), promoted AML in mice. Mechanistically, loss of KDM5D, a chromosome Y–specific histone 3 lysine 4 demethylase in both humans and mice, partially recapitulated mLOY in DNA damage and leukemogenesis. Thus, our study validates mLOY as a functional driver for clonal hematopoiesis and leukemogenesis.

/pdf/mosaic-loss-of-chromosome-y-promotes-leukemogenesis-and-1wc0xoet.pdf

Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis

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Characteristics and prognostic significance of genetic mutations in acute myeloid leukemia based on a targeted next-generation sequencing technique

Difference in gene mutation profile in patients with refractory/relapsed versus newly diagnosed acute myeloid leukemia based on targeted next-generation sequencing.

Responses to ALK Inhibitor Treatments in a Patient with Non-Small Cell Lung Cancer Harboring a Novel HPCAL1-ALK Fusion Variant: A Case Report.

Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis